The Role of TNF Alpha in Obesity

TNF Alpha 在肥胖中的作用

• 批准号: 7795141
• 负责人: STEPHEN C WOODS
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795141
• 关键词: Adipocytes; Adipose tissue; Animal Model; Animals; Binding; Body Weight Changes; Body fat; Brain; Cardiovascular Diseases; Cell membrane; Central obesity; Chronic; Cleaved cell; Development; Diet; Dose; Eating; Endothelial Cells; Energy Intake; Energy Metabolism; Enzymes; Etiology; Fat-Restricted Diet; Fatty acid glycerol esters; Genotype; Glucose; Goals; Homeostasis; Hypothalamic structure; Inflammatory; Infusion procedures; Injection of therapeutic agent; Insulin; Insulin Resistance; Lead; Link; Membrane; Mesentery; Metabolic; Metabolic syndrome; Mus; Obesity; Outcome; Phenotype; Plasma; Population; Recruitment Activity; Relative (related person); Risk Factors; Role; Series; Signal Transduction; Signaling Molecule; Site; Source; Symptoms; TNF gene; TNF-alpha converting enzyme; Testing; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Ventricular; Weight Gain; Wild Type Mouse; base; cytokine; energy balance; feeding; glucose tolerance; insulin sensitivity; insulin signaling; intraperitoneal; macrophage; migration; public health relevance; receptor; research study; subcutaneous

DESCRIPTION (provided by applicant): This project is based upon the relatively recent realization that obesity, and especially visceral obesity, is a chronic inflammatory condition characterized by migration of high numbers of macrophages into the adipose tissue, with consequent increased local and plasma levels of cytokines. The consequences of these changes are thought to be causally linked to insulin resistance and the metabolic syndrome. In particular, high levels of inflammatory cytokines in the plasma, and especially tumor necrosis factor-1 (TNF1), have been recognized as an important risk factor for several metabolic and cardiovascular disorders, and in animal models reductions in TNF1 ameliorate many of the deleterious effects of obesity. There is compelling evidence that an important initial step along the road to obesity is an increase of TNF1 synthesis by adipose tissue, and that this in turn stimulates preadipocytes and local endothelial cells to recruit macrophages into the adipose tissue. This continues as a spiraling situation of increased inflammatory signaling molecules and mutual cross-stimulation of adipocytes and macrophages. TNF1 and other inflammatory signaling molecules eventually reach high enough levels to be detected in the plasma. Because TNF1 from adipose tissue circulates throughout the body and reaches diverse receptor populations, the role of TNF1 activity at specific sites, and at selective receptors, in the etiology of obesity and insulin resistance is not known. We have preliminary evidence that one important site of TNF1 action is in the brain, where it interacts with other signals that influence energy intake. Proposed experiments will (1) test the hypothesis that TNF1 acts in the brain to control energy homeostasis, and specifically that TNF1 action within the brain increases central insulin sensitivity while simultaneously decreasing systemic insulin sensitivity. A related hypothesis is that TNF1 is more effective in the brains of animals that have systemic insulin resistance, such as high-fat diet (HFD) induced obesity; (2) assess the relative contributions of free (unbound; soluble) TNF1 and membrane-bound TNF1 in the effects of TNF1 on energy balance; and (3) determine whether subcutaneous adipose tissue, mesenteric adipose tissue, or adipose tissue-resident macrophages are individually (or in combination) sufficient sources of TNF1 to elicit symptoms of the metabolic syndrome. Experiments will use normal (wild-type) mice and mice lacking TNF1 or its receptors or else mice lacking TACE, the enzyme that cleaves membrane-bound TNF1 to free TNF1. PUBLIC HEALTH RELEVANCE: Visceral obesity is recognized to be a chronic inflammatory condition characterized by high numbers of macrophages in adipose tissue and elevated plasma levels of cytokines such as tumor necrosis factor-1 (TNF1) that is thought to lead to insulin resistance. Proposed experiments will test the hypothesis that TNF1 acts in the brain to control food intake and systemic insulin sensitivity, and determine which form of TNF1 is critical. Experiments will use normal (wild-type) mice and mice lacking TNF1 or its receptors.

描述（由申请人提供）：该项目基于相对较新的认识，即肥胖，尤其是内脏肥胖，是一种慢性炎症状况，其特征是大量巨噬细胞迁移到脂肪组织中，因此局部和血浆的细胞因子水平升高。这些变化的后果被认为与胰岛素抵抗和代谢综合征有因果关系。特别是，血浆中的炎症细胞因子高水平，尤其是肿瘤坏死因子1（TNF1），已被认为是多种代谢和心血管疾病的重要危险因素，而在动物模型中，TNF1减少了TNF1的减少，可以改善肥胖症的许多有害影响。有令人信服的证据表明，沿着肥胖道路的重要初步步骤是脂肪组织的TNF1合成增加，而这又刺激了前脂肪细胞和局部内皮细胞，以将巨噬细胞募集到脂肪组织中。这继续是炎症信号分子增加以及脂肪细胞和巨噬细胞的相互交叉刺激的螺旋状况。 TNF1和其他炎症信号分子最终达到了足够高的水平，可以在血浆中检测到。由于脂肪组织的TNF1在整个体内循环并达到不同的受体种群，因此尚不清楚TNF1活性在特定部位和选择性受体的作用，而在选择性受体中的作用尚不清楚。我们有初步证据表明，TNF1作用的一个重要部位是在大脑中，它与影响能量摄入的其他信号相互作用。提出的实验将（1）检验以下假设：TNF1在大脑中起作用以控制能量稳态，特别是在大脑中的TNF1作用会增加中央胰岛素敏感性，同时降低全身性胰岛素敏感性。一个相关的假设是，TNF1在具有全身性胰岛素抵抗的动物的大脑中更有效，例如高脂饮食（HFD）诱导的肥胖。 （2）评估自由（未结合）TNF1和膜结合的TNF1对TNF1对能量平衡的影响的相对贡献； （3）确定皮下脂肪组织，肠系膜脂肪组织或脂肪组织居民巨噬细胞是否单独（或组合）足够的TNF1来源来引起代谢综合征的症状。实验将使用缺乏TNF1或其受体的正常（野生型）小鼠，或者缺少TACE的小鼠，该酶是将膜结合的TNF1裂解至游离TNF1的酶。公共卫生相关性：内脏肥胖被认为是一种慢性炎症疾病，其特征是脂肪组织中的巨噬细胞数量高，血浆升高的细胞因子（例如肿瘤坏死因子1（TNF1））升高，被认为会导致胰岛素抵抗。提出的实验将检验以下假设：TNF1在大脑中起作用以控制食物摄入和全身性胰岛素敏感性，并确定TNF1的哪种形式至关重要。实验将使用缺乏TNF1或其受体的正常（野生型）小鼠和小鼠。